Marjolein H Willemsen

University of Adelaide, Tarndarnya, South Australia, Australia

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Publications (45)323.67 Total impact

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    ABSTRACT: De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (Structural Maintenance of Chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male or female patients. However, recently we and others reported loss-of-function mutations in females with ID and epilepsy. Here we present the detailed phenotype of two females with de novo loss-of-function mutations in SMC1A, including a de novo mutation of single base deletion (c.2364del, p.(Asn788Lysfs*10)), predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product (p.(Leu808Argfs*6)). By combining our patients with the other recently reported females carrying SMC1A loss-of-function mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS -and caused by de novo SMC1A loss-of-function mutations.
    No preview · Article · Jan 2016 · Clinical Genetics
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    ABSTRACT: This report is regarding a Dutch female with microcephaly, mild intellectual disability (ID), gonadal dysgenesis and dysmorphic facial features with synophrys. Upon genotyping, an ∼455 kb de novo deletion encompassing the first exon of NRXN1 was found. Bidirectional sequencing of the coding exons of the NRXN1 alpha isoform was subsequently performed to investigate the possibility of a pathogenic mutation on the other allele, but we could not find any other mutation. Previously, many heterozygous mutations as well as microdeletions in NRXN1 were shown to be associated with ID, autism, schizophrenia, and other psychiatric and psychotic disorders. Our results are in agreement with other reports that show that NRXN1 deletions can lead to ID, microcephaly and mild dysmorphic features. However, this is the first report of gonadal dysgenesis being associated with such deletions. It is not clear whether there is a causal relationship between the NRXN1 deletion and gonadal dysgenesis, but it is of interest that the FSHR gene, which encodes the follicle-stimulating hormone receptor causative correlation that is mutated in ovarian dysgenesis, is located proximal to the NRXN1 gene. Given that most of the females carrying NRXN1 deletions have been diagnosed at a prepubertal age, gynecologic screening of female carriers of a NRXN1 deletion is warranted.
    Full-text · Article · Oct 2015 · Genetics Research
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    ABSTRACT: The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.
    Full-text · Article · Aug 2015 · European journal of human genetics: EJHG
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    ABSTRACT: Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3β, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.
    Full-text · Article · Jul 2015 · The Journal of clinical investigation
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    ABSTRACT: Autism and behavioral characteristics in adults with Dravet syndrome (DS) have rarely been systematically studied. Three scales were used to assess the outcomes of DS in adulthood in terms of autism and behavior. All the adult patients with DS, nine male and four female, aged between 18 and 60years, living at the Epilepsy Center Kempenhaeghe in The Netherlands were included in the study. In addition, the past medical history of each patient was systematically screened for diagnoses like autism, Pervasive Development Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD), hyperactivity, Attention Deficit Hyperactivity Disorder (ADHD), and self-mutilation. Information concerning past and current use of psychoactive drugs was also evaluated. Eight patients (61.5%) were classified as having autism spectrum disorder (ASD) according to the AVZ-R or according to the medical record. Self-mutilation was seen in four patients (30.8%), hyperactivity in none. Three patients (23.1%) currently used psychoactive drugs. Autism spectrum disorders persist in adult patients with DS, while certain characteristics associated with behavioral problems, such as hyperactivity or use of psychoactive medication, seem to be less prominent than in childhood. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · May 2015 · Epilepsy & Behavior

  • No preview · Article · Apr 2015 · Epilepsia
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    ABSTRACT: Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels. The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype-phenotype correlations of these and other cases were related to the functional analyses. The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel. Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Full-text · Article · Feb 2015 · Journal of Medical Genetics
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    ABSTRACT: Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.Molecular Psychiatry advance online publication, 24 February 2015; doi:10.1038/mp.2015.5.
    Full-text · Article · Feb 2015 · Molecular Psychiatry
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    ABSTRACT: We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · The American Journal of Human Genetics
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    ABSTRACT: X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4-/- mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.Molecular Psychiatry advance online publication, 3 February 2015; doi:10.1038/mp.2014.193.
    Full-text · Article · Feb 2015 · Molecular Psychiatry
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    ABSTRACT: Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.European Journal of Human Genetics advance online publication, 26 November 2014; doi:10.1038/ejhg.2014.253.
    Full-text · Article · Nov 2014 · European journal of human genetics: EJHG
  • Marjolein H Willemsen · Tjitske Kleefstra
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    ABSTRACT: - Until recently, the cause of intellectual disability remained unknown in at least 50% of affected people.- The various causes require diverse healthcare needs. Knowing the cause enables specific anticipation on these.- Severe intellectual disability (IQ < 50) usually has a genetic cause. The majority can be explained by de novogene mutations and chromosomal aberrations.- In recent years, rapid advances in genetic diagnostics have provided great new opportunities. The introduction of array analysis has allowed the genome-wide detection of chromosomal aberrations. Until recently, the detection of monogenic causes of intellectual disability was highly dependent on the recognisability of the phenotype and specific DNA diagnostic testing of single genes. The introduction of exome sequencing enables testing of all genes simultaneously in a single test.- It is expected that exome sequencing will be followed up by genome sequencing in the near future, and this will become the first tier diagnostic test. Detection of chromosomal aberrations is also possible with this technique.- These developments may lead to a significant increase in the percentage of explained intellectual disability, from 50% in the past to 80%.
    No preview · Article · Nov 2014 · Nederlands tijdschrift voor geneeskunde
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    ABSTRACT: Microdeletions of the 5q11.2 region are rare; in literature only two patients with a deletion in this region have been reported so far. In this study, we describe four additional patients and further define this new 5q11.2 microdeletion syndrome. A comparison of the features observed in all six patients with overlapping 5q11.2 deletions showed a phenotypic spectrum that overlaps with CHARGE syndrome and 22q11.2 deletion syndrome including choanal atresia, developmental delay, heart defects, external ear abnormalities, and short stature. No colobomas or abnormalities of semicircular canals and olfactory nerves were reported. Two male patients had genital abnormalities. We estimated a 2.0 Mb (53.0–55.0 Mb) Shortest Region of Overlap (SRO) for the main clinical characteristics of the syndrome. This region contains nine genes and two non-coding microRNAs. In this region DHX29 serves as the candidate gene as it encodes an ATP-dependent RNA-helicase that is involved in the initiation of RNA translation. Screening a small cohort of 14 patients who presented the main features, however, did not reveal any pathogenic abnormalities of DHX29. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2014 · American Journal of Medical Genetics Part A
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    ABSTRACT: Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.
    Full-text · Article · Oct 2014 · Human Genetics
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    ABSTRACT: Purpose: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis. Methods: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization. Results: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain. Conclusion: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466.
    No preview · Article · Sep 2014 · Genetics in medicine: official journal of the American College of Medical Genetics
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    ABSTRACT: Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.
    No preview · Article · Jun 2014 · Nature
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    ABSTRACT: Kinesin superfamily (KIF) genes encode motor proteins that have fundamental roles in brain functioning, development, survival and plasticity by regulating the transport of cargo along microtubules within axons, dendrites and synapses. Mouse knockout studies support these important functions in the nervous system. The role of KIF genes in intellectual disability (ID) has so far received limited attention, although previous studies have suggested that many ID genes impinge on synaptic function. By applying next-generation sequencing (NGS) in ID patients, we identified likely pathogenic mutations in KIF4A and KIF5C. To further confirm the pathogenicity of these mutations, we performed functional studies at the level of synaptic function in primary rat hippocampal neurons. Four males from a single family with a disruptive mutation in the X-linked KIF4A (c.1489-8_1490delins10; p.?- exon skipping) showed mild to moderate ID and epilepsy. A female patient with a de novo missense mutation in KIF5C (c.11465A>C; p.(Glu237Lys)) presented with severe ID, epilepsy, microcephaly and cortical malformation. Knock-down of Kif4a in rat primary hippocampal neurons altered the balance between excitatory and inhibitory synaptic transmission, whereas the mutation in Kif5c affected its protein function at excitatory synapses. Our results suggest that mutations in KIF4A and KIF5C cause ID by tipping the balance between excitatory and inhibitory synaptic excitability.
    Full-text · Article · May 2014 · Journal of Medical Genetics
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    ABSTRACT: The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults.
    Full-text · Article · Mar 2014 · The Journal of clinical investigation
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    ABSTRACT: Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next-generation sequencing, for the large majority of cases no molecular diagnosis can be established. Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.
    Full-text · Article · Feb 2014 · Nature Genetics
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    ABSTRACT: We report a consanguineous Pakistani family with a severe congenital microcephaly syndrome resembling Seckel syndrome and Jawad syndrome. The affected individuals in this family were born to consanguineous parents of whom the mother presented with mild intellectual disability (ID), epilepsy and diabetes mellitus. The two living affected brothers presented with microcephaly, white matter disease of the brain, hyponychia, dysmorphic facial features with synophrys, epilepsy, diabetes mellitus and ID. Genotyping with a 250K SNP array in both affected brothers revealed an 18MB homozygous region on chromosome 18p11.21q12.1 encompassing the SCKL2 locus of Seckel and Jawad syndrome. Sequencing of the RBBP8, underlying Seckel and Jawad syndrome, identified the novel mutation c.919A>G, p.Arg307Gly, segregating in a recessive manner in the family. In addition, in the two affected brothers and their mother we have also found a heterozygous 607kb deletion, encompassing exons 13-19 of NRXN1. Bidirectional sequencing of the coding exons of NRXN1 did not reveal any other mutation on the other allele. It thus appears that the phenotype of the mildly affected mother can be explained by the NRXN1 deletion, whereas the more severe and complex microcephalic phenotype of the two affected brothers is due to the simultaneous deletion in NRXN1 and the homozygous missense mutation affecting RBBP8.
    Full-text · Article · Jan 2014 · Gene

Publication Stats

1k Citations
323.67 Total Impact Points

Institutions

  • 2015
    • University of Adelaide
      • School of Paediatrics and Reproductive Health
      Tarndarnya, South Australia, Australia
    • Maastricht Universitair Medisch Centrum
      Maestricht, Limburg, Netherlands
    • Max Planck Institute for Molecular Genetics
      • Department of Human Molecular Genetics
      Berlín, Berlin, Germany
  • 2009-2015
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
    • Radboud University Nijmegen
      Nymegen, Gelderland, Netherlands